Respiratory bronchiolitis is the initial lesion seen in smokers [12]. The inflammatory process may progress in susceptible people to glandular enlargement in bronchi, goblet cell metaplasia, smooth muscle hypertrophy, inflammation in membranous bronchioles, worsening respiratory bronchiolitis, and parenchymal involvement with emphysema [13]. The progression of COPD is strongly associated with an increase in the volume of tissue in the wall and the accumulation of inflammatory
mucous exudates in the lumen of small airways [14]. Normally, a relative balance exists between destructive proteolytic enzymes, which are released in the lung as a result of inflammation, and various inhibitory, antiproteolytic substances, which act to dampen the response and limit the damage [15]. In some cigarette smokers, there may be a genetic tendency favoring a greater inflammatory and destructive response to certain elements of cigarette smoke. Population studies show a definite familial tendency toward COPD [16], and pulmonary function comparison studies of identical twins suggest a genetic susceptibility [17].

COPD is characterized by chronic inflammation throughout the airways, parenchyma, and pulmonary vasculature. Macrophages, T lymphocytes (predominately CD8+), and neutrophils are increased in various parts of the lung [18]. Activated inflammatory cells release a variety of mediators—including leukotriene B4, interleukin-8, tumor necrosis factor-α, and others—capable of damaging lung structures and/or sustaining neutrophilic inflammation [5]. There is a relationship between the extent of airway occlusion by inflammatory mucus exudates and the severity of COPD [14].

Expiratory airflow obstruction results from structural airway narrowing as well as functional narrowing due to loss of radial distending forces on the airways. Inflammatory edema, excessive mucus, and glandular hypertrophy are responsible for intrinsic obstruction of airways. Destruction of alveolar walls causes loss of elastic recoil and airflow obstruction, which increases in a dynamic fashion with expiratory effort.

The pathophysiologic consequences of severe, chronic airflow obstruction in the lung include (a) reduced flow rates that limit minute ventilation; (b) maldistributed ventilation, resulting in wasted ventilation (high ventilation-perfusion [[V with dot above]/[Q with dot above]] mismatch) and impaired gas exchange (low [V with dot above]/[Q with dot above] mismatch) [19]; (c) increased airway resistance, which causes increased work of breathing [19]; and (d) air trapping and hyperinflation, which alter the geometry of the respiratory muscles and place them at a mechanical disadvantage. The maximum force that they are capable of generating is decreased, which may predispose them to fatigue [20]. In addition to these factors, some patients with COPD may have a blunted respiratory center drive, which further predisposes them to carbon dioxide retention [21].

A chronic productive cough and dyspnea on exertion are the two symptoms most commonly associated with COPD. However, a history of a chronic productive cough is nonspecific and may result from a variety of other conditions. Previous studies indicated that there was little correlation found between a chronic productive cough (reflecting large-airway mucus hypersecretion) and the development of significant airflow limitation (predominantly a manifestation of disease of small airways less than 2 mm in diameter) [22]. However, recent studies have shown a consistent association between chronic mucus hypersecretion and both an accelerated decline in FEV₁ and an increased risk of subsequent hospitalization [23]. A history of dyspnea on exertion in a heavy cigarette smoker should always raise the possibility of COPD, which can then be confirmed by objective investigations.

The physical examination can distinguish patients who should undergo objective laboratory testing, but it is less accurate than PFTs in detecting and quantifying the severity of COPD [24]. The most useful physical finding is a definite decrease in breath sound intensity [25,26]. Other suggestive clinical signs include hyperinflation, prolonged forced expiratory time, and wheezing.

A combative, confused, or obtunded patient should alert the physician to the possibility of hypercapnia or hypoxia. Respiratory muscle fatigue is heralded by new onset of paradoxical respiratory motion or respiratory alternans [27]. During normal inspiration, the rib cage moves upward and outward, and the anterior abdominal wall moves outward. With diaphragmatic fatigue, the anterior abdominal wall may move inward during inspiration and outward during expiration. Respiratory alternans describes alternate abdominal (diaphragmatic) breathing and rib cage (intercostal) breathing. When overt, this condition can be detected clinically by observing dramatic shifts in relative movement of the abdomen and rib cage every few breaths.

Radiographic findings may include (a) hyperinflation with flattened diaphragmatic domes and increased retrosternal and retrocardiac air space; (b) one of two distinctly different bronchovascular patterns, vascular attenuation or prominence of lung markings; (c) enlarged hilar pulmonary arteries and right ventricular enlargement; and (d) regional hyperlucency and bullae [28]. Radiographic studies have low sensitivity for the diagnosis of mild COPD [29].

Computed tomography scanning of the chest is superior to the chest radiograph in diagnosing emphysema and determining the nature and the extent of the disease [29]. Centrilobular emphysema is characterized by the upper lobe distribution of focal areas of low attenuation usually less than 1 cm in diameter. Panlobular emphysema is frequently more recognized in the lower lobes and there is a generalized decrease in lung markings with few blood vessels.

In patients presenting with acute deterioration in respiratory status, a chest radiograph may exclude reversible conditions such as pneumonia, pleural effusion, pneumothorax, atelectasis, and pulmonary edema. However, the diagnostic yield of routine radiographs is low [30]. In the intensive care unit (ICU), technical factors limit the quality of the chest films, making interpretation of a portable anteroposterior film even more difficult. Nevertheless, these studies provide valuable information, particularly in patients receiving mechanical ventilation.

A decrease in the ratio of FEV₁ to forced vital capacity is the hallmark of obstructive airways disease and is useful in the diagnosis of mild disease. However, it is the FEV₁ that is correlated with clinical outcome and mortality [23]. Hypercapnic respiratory failure from COPD is extremely unlikely unless FEV₁ is less than 1.3 L [31] and is usually not observed unless FEV₁ is less than 1 L. COPD is also associated with an increase in total lung capacity and residual volume and a reduction in carbon monoxide diffusing capacity [32].

PFTs are essential for the diagnosis and estimating the severity of COPD; on the other hand, ABG values provide the data
necessary to diagnose and quantitate the severity of respiratory failure. The patient with severe COPD typically presents with an elevated arterial carbon dioxide tension (PaCO₂), substantially decreased arterial oxygen tension (PaO₂), and an alveolar–arterial oxygen tension gradient that is significantly increased [33].

Once COPD is diagnosed, smoking cessation is the most important and obvious first step in management. The annual decline in FEV₁ has been demonstrated to be less in ex-smokers than in current smokers [6]. The success of smoking cessation programs is limited, with a 70% to 80% relapse rate in the first year. However, nicotine replacement therapy, the antidepressant bupropion, and repeated counseling are effective in increasing quit rates [39]. The addition of varenicline, an α₄β₂ nicotinic receptor partial agonist, has improved cigarette-smoking quit rates [40]. Annual influenza vaccination is a useful, cost-effective preventive measure and has been shown to decrease morbidity and mortality related to influenza even among patients with chronic respiratory disease [41,42]. Data regarding the benefit of pneumococcal vaccination are limited to bacteremic pneumococcal infection, but a decrease in hospitalizations and deaths among vaccinated patients with COPD has been observed in observational studies [43].

Inhaled bronchodilators improve airflow obstruction, although to a less marked degree than in asthmatic patients, and improve exercise capacity and quality of life [44]. Although β-agonists and the anticholinergic agent ipratropium bromide are efficacious, the combination is more effective than either of the two agents alone [45]. Long-acting β₂-adrenergic agonists in combination with ipratropium or theophylline are superior to either agent alone, and a long-acting β₂-adrenergic agonist combined with ipratropium is more effective than the short-acting β₂-adrenergic agonist plus ipratropium [46,47]. A long-acting β₂-adrenergic agonist appears to offer the additional benefit of extending the time to an exacerbation [47]. Long-acting anticholinergics have been demonstrated to improve lung function, reduce exacerbations, and improve health-related quality of life [48,49]. In addition to some bronchodilator effects, theophylline may have beneficial effects on diaphragmatic strength, resistance to fatigue, and central nervous system (CNS) respiratory drive [50,51]. This agent produces a clinical benefit in some patients with COPD [52] but, with its narrow therapeutic window, the potential for toxicity
must be recognized. All categories of bronchodilators have been shown to increase exercise capacity in COPD without necessarily producing significant changes in FEV₁ probably by decreasing dynamic hyperinflation. Regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting bronchodilators, but more expensive. They safely attenuate airflow obstruction, decrease the frequency and severity of symptoms by reducing the amount of dynamic hyperinflation, and improve quality of life [53].

Although oral corticosteroids are not routinely recommended in the chronic management of patients with COPD, a small subgroup of patients does benefit [54]. A corticosteroid trial, with PFTs before and after a 2-week course of 20 to 40 mg prednisone daily, has been recommended in the past to identify these patients. More recent studies suggest, however, that this is a poor predictor of long-term response to inhaled corticosteroids [55]. Several studies have documented little effect on the rate of lung function decline with inhaled corticosteroid therapy, but the severity and number of exacerbations may be reduced, especially among patients with frequent exacerbations [56,57]. Short-term treatment with a combined inhaled glucocorticosteroid and long-acting β-agonist resulted in greater control of lung function and symptoms than combined anticholinergic and short-acting β-agonist [58]. Analysis of a number of placebo-controlled trials of inhaled corticosteroids has demonstrated a reduction in all-cause mortality by about 25% relative to placebo [59]. Stratification by individual trials and adjustments for age, sex, baseline postbronchodilator percentage predicted FEV₁, smoking status, and body mass index do not materially change the results. Former smokers and women seem to benefit the most.

There is a growing body of evidence to suggest that the use of a combination of inhaled corticosteroids and long-acting β₂-agonists improves lung function, symptoms, and health status and reduces exacerbations in patients with moderate-to-severe COPD [60]. There may also be a survival benefit. A subsequent post hoc analysis of the Toward a Revolution in COPD Health (TORCH) study indicated that pharmacotherapy with salmeterol plus fluticasone propionate, or the components, reduced the rate of decline of FEV₁ in patients with moderate-to-severe COPD, thus slowing disease progression [61].

The addition of a combination of inhaled corticosteroid and long-acting β₂-agonist (salmeterol plus fluticasone) to a long-acting anticholinergic (tiotropium) improved lung function, health status and reduced hospitalizations compared with the use of a long-acting anticholinergics alone [62]. Therapy with tiotropium added to other respiratory medication (mainly a combination of inhaled corticosteroid and long-acting β₂-agonist) was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV₁ [63].

Long-term oxygen therapy used for at least 15 hours per day in patients with severe COPD and hypoxia when breathing room air is associated with prolonged survival and improved quality of life, increasing life span by 6 to 7 years [64,65]. Oxygen therapy is recommended for patients with a PaO₂ of less than 55 mm Hg and those with a PaO₂ of 55 to 59 mm Hg who have polycythemia or right-sided heart failure. Significant increases in PaCO₂ usually do not occur as a result of this therapy [66].

Pulmonary rehabilitation programs have been demonstrated to improve exercise tolerance and reduce dyspnea and should be part of routine management for patients with significant COPD [67,68,69]. Nocturnal negative-pressure ventilatory assistance has been used to rest respiratory muscles [70]. Whether this intervention is beneficial is unclear, as a large controlled trial failed to demonstrate improvement in exercise tolerance, ABG values, or quality of life [71]. Successful therapeutic results with nocturnal noninvasive positive-pressure assistance in COPD patients have not been uniformly reported, but there may be a role for selected patients [72].